Cu(I)-catalyzed decarboxylative aldol-type and Mannich-type reactions for asymmetric construction of contiguous trisubstituted and quaternary stereocenters

The catalytic asymmetric decarboxylative aldol-type reaction between aldehydes and cyanocarboxylic acids and Mannich-type reaction between aldimines and cyanocarboxylic acids were developed. alpha,alpha,beta-Trisubstituted-beta-hydroxy nitriles bearing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate enantio- and diastereoselectivity in the presence of 10 mol % CuOAc-TANIAPHOS (or DTBM-SEGPHOS) complex in the aldol-type reaction. alpha,alpha,beta-Trisubstituted-beta-amino nitriles containing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate to high enantio- and diastereoselectivity using 5 mol % CuOAc-(R)-DTBM-SEGPHOS complex in the Mannich-type reaction. These reactions proceed through Cu(I)-catalyzed decarboxylative nucleophile generation, followed by the addition of the resulting chiral Cu-ketenimide to aldehydes or imines. Because the reactions proceed under very mild conditions at nearly neutral pH, the reactions are applicable to a wide range of substrate combinations, including both aromatic and aliphatic substrates. Finally, alpha,alpha,beta-trisubstituted-beta-amino nitriles were converted to beta(2,2,3)-amino acid derivatives through simple acidic hydrolysis without any racemization and epimerization. (C) 2011 Elsevier Ltd. All rights reserved.